Methods and Systems for Ultrasound Assisted Delivery of a Medicant to Tissue

ABSTRACT

This disclosure provides methods and systems for ultrasound assisted delivery of a medicant to tissue. The delivery of the medicant is enhanced by the application of high intensity ultrasound pulses, which generate an intertial cavitation effect, an acoustic streaming effect, or both. This disclosure also provides methods and systems for alleviating pain or swelling associated with the application of ultrasound energy by delivering an anesthetic across a stratum corneum layer according to the methods described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent application Ser. No. 12/116,810, filed May 7, 2008, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/916,509, filed May 7, 2007, the entire contents of which are incorporated by reference herein in their entirety.

BACKGROUND

Skin comprises at least four distinct layers of tissue: the nonviable epidermis (i.e., the stratum corneum), the viable epidermis, the dermis, and subcutaneous connective tissue and fat. The circulatory system lies in the dermis and tissues below the dermis. As skin generally prohibits the transport of macromolecules to the dermis and tissues below the dermis, needles are often required to administer macromolecular medicants.

Ultrasound has long been used for diagnostic imaging applications. More recently however, several new therapeutic applications for ultrasound are being discovered. Among the applications for ultrasound, enhanced transdermal medicant delivery and/or effectiveness has received considerable attention. To date, however, the better part of ultrasound-enhanced medicant delivery and/or effectiveness efforts have been focused on ultrasound at frequencies below 200 kHz, and prior systems have directed ultrasound at single layers of tissue.

Trandermal delivery of medicants is limited primarily to the difficult-to-penetrate nature of the stratum corneum layer of skin. The stratum corneum layer forms a barrier that keeps moisture in and keeps practically everything else out. Accordingly, attempts to topically apply a medicant and deliver the medicant across the stratum corneum layer to tissue located beneath it must overcome this barrier property in order to be effect.

The bioavailability of topically applied medicants is typically very low. For example, the bioavailability of topically applied lidocaine is approximately 3%. See, Campbell, et al. J. Pharm. Sci. 91(5), pp. 1343-50 (May 2002). In other words, more than 30 times the desired amount of lidocaine needs to be applied topically for the desired effect. In the case of an expensive medicant or a medicant having various side effects, it is undesirable to require application of such an excess of medicant in order to have the desired effect.

Workarounds for this limited bioavailability of topically applied medicants generally include physically puncturing the skin, which is undesirable, because some patients can have aversion to the needles associated with such procedures.

Low-frequency sonophoresis is a known method for enhancing transdermal drug delivery. However, these existing methods employ low-frequencies, low peak intensities, require long application times, or some combination of these to achieve improved transdermal drug delivery.

Accordingly, a need exists for new systems and methods that overcome the aforementioned shortcomings.

SUMMARY

This invention improves upon the prior art by providing methods and systems uniquely capable of enhancing medicant delivery and/or effectiveness through the use of energy (e.g., acoustic energy). An exemplary embodiment predictably disrupts membranes and mechanically and thermally modulates cells and tissues. In exemplary embodiments, the methods and systems disclosed herein are capable of modulating multiple layers of tissue (e.g., a plurality of depths within a cell membrane or tissue).

The methods and systems disclosed herein contemplate delivering focused, unfocused, and/or defocused ultrasound energy to a region of interest at various spatial and temporal energy settings, in the range of about 100 kHz to about 500 MHz. In an exemplary embodiment, the energy is acoustic energy (e.g., ultrasound). In other exemplary embodiments, the energy is photon based energy (e.g., IPL, LED, laser, white light, etc.), or other energy forms, such radio frequency electric currents, or various combinations of acoustic energy, electromagnetic energy and other energy forms or energy absorbers such as cooling.

Medicants can be first introduced to the region of interest by diffusion, circulation, and/or injection, to name a few. In other embodiments, the methods and systems disclosed herein are configured to interact with chemicals naturally occurring or already existing within the body in terms of, for example, concentration, function, and cell division properties.

An exemplary system for enhancing medicant delivery and/or effectiveness comprises a control system, a probe, and a display or indicator system. The probe can comprise various probe and/or transducer configurations. In an exemplary embodiment, the probe delivers focused, unfocused, and/or defocused ultrasound energy to the region of interest. Imaging and/or monitoring may alternatively be coupled and/or co-housed with an ultrasound system contemplated by the present invention.

The control system and display system can also comprise various configurations for controlling probe and system functionality, including for example, a microprocessor with software and a plurality of input/output devices, a system for controlling electronic and/or mechanical scanning and/or multiplexing of transducers, a system for power delivery, systems for monitoring, systems for sensing the spatial position of the probe and/or transducers, and systems for handling user input and recording treatment results, among others.

In accordance with an exemplary embodiment, a coupling agent, comprised of at least one of a gel, cream, liquid, emulsion or other compound, is used to couple the probe to a patient's body. In an exemplary embodiment, the coupling agent contains medicants that are delivered to the patient's body during the emission of energy from the probe.

In one aspect, this disclosure provides a method for ultrasound assisted delivery of a medicant through a stratum corneum layer of a skin surface. The method can include: administering the medicant to a skin surface; coupling an ultrasound transducer to the medicant and the skin surface; and applying a first pulse acoustic energy field from the ultrasound transducer to the skin surface. The first pulse acoustic energy field can have a frequency from 1 MHz to 30 MHz, a peak intensity from 100 W/cm² to 100 kW/cm², and a pulse width from 33 nanoseconds to 5 seconds. The first pulsed acoustic energy field can generate inertial cavitation, acoustic streaming, or a combination thereof in the stratum corneum layer and drive the medicant through the stratum corneum layer.

In another aspect, this disclosure provides a method for reducing or eliminating pain generated by ultrasound treatment. The method can include: applying a coupling medium comprising a medicant to a skin surface above a region of intere, the medicant comprising an anesthetic configured to numb a tissue in the region of interest; coupling an ultrasound energy source to the coupling medium, the skin surface, and the region of interest; directing a first acoustic energy field from the ultrasound energy source into the skin surface, thereby delivering the medicant into the tissue in the region of interest and numbing the tissue in a portion of the region of interest; and directing a second acoustic energy field to a target volume in the tissue in the region of interest, the second acoustic energy field ablating the tissue in the target volume, the medicant reducing or eliminating pain generated by the ablating of the tissue.

In yet another aspect, this disclosure provides a method of ultrasound assisted transdermal drug delivery. The method can include: contacting a skin surface with a coupling medium comprising a non-anesthetic medicant and an anesthetic; coupling an ultrasound energy source to the coupling medium and the skin surface; and applying a first pulsed acoustic energy field from the ultrasound transducer to the skin surface. The first pulse acoustic energy field can have a peak intensity from 100 W/cm² to 100 kW/cm². The first pulsed acoustic energy field can drive the medicant and the anesthetic across a stratum corneum layer of the skin surface and into an epidermis layer beneath the skin surface. The anesthetic can alleviate pain or swelling associated with the application of the first pulsed acoustic energy field.

The foregoing and other aspects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration a preferred aspect of the disclosure. Such aspect does not necessarily represent the full scope of the disclosure, however, and reference is made therefore to the claims and herein for interpreting the scope of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter of the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to structure and method of operation, may best be understood by reference to the following description taken in conjunction with the claims and the accompanying drawing figures, in which like parts may be referred to by like numerals, and:

FIG. 1A illustrates a block diagram of a method for modulating medicants in accordance with an exemplary embodiment of the present invention;

FIG. 1B illustrates a block diagram of a system for modulating medicants in accordance with an exemplary embodiment of the present invention;

FIG. 2 illustrates a block diagram of a treatment system comprising an ultrasound treatment subsystem combined with additional subsystems and methods of treatment monitoring and/or treatment imaging as well as a secondary treatment subsystem in accordance with an exemplary embodiment of the present invention;

FIG. 3 illustrates a schematic diagram of a system for modulating medicants in accordance with an exemplary embodiment of the present invention;

FIGS. 4A, 4B, 4C, 4D and 4E illustrate cross-sectional diagrams of an exemplary transducer in accordance with various embodiments of the present invention; and

FIGS. 5A, 5B, and 5C illustrate block diagrams of an exemplary control system in accordance with exemplary embodiments of the present invention.

FIG. 6A illustrates an ultrasound assisted drug delivery probe and a first stage of a method of its use, according to one aspect of the present disclosure.

FIG. 6B illustrates an ultrasound assisted drug delivery probe and a second stage of a method of its use, according to one aspect of the present disclosure.

FIG. 6C illustrates an ultrasound assisted drug delivery probe and a third stage of a method of its use, according to one aspect of the present disclosure.

FIG. 6D illustrates an ultrasound assisted drug delivery probe and a fourth stage of a method of its use, according to one aspect of the present disclosure.

FIG. 7A illustrates an ultrasound assisted drug delivery probe and a first stage of a method of its use, according to one aspect of the present disclosure.

FIG. 7B illustrates an ultrasound assisted drug delivery probe and a second stage of a method of its use, according to one aspect of the present disclosure.

FIG. 7C illustrates an ultrasound assisted drug delivery probe and a third stage of a method of its use, according to one aspect of the present disclosure.

FIG. 7D illustrates an ultrasound assisted drug delivery probe and a fourth stage of a method of its use, according to one aspect of the present disclosure.

FIG. 8 illustrates a set of components for use in an ultrasound assisted drug delivery system, according to one aspect of the present disclosure.

FIG. 9 is a flowchart illustrating methods of ultrasound assisted drug delivery, according to one aspect of the present disclosure.

FIG. 10A is a picture showing the result of applying a method according to one aspect of the present disclosure with and without a 5% lidocaine ointment, as shown in Example 1.

FIG. 10B is a picture showing the result of applying a method according to one aspect of the present disclosure with and without a 5% lidocaine ointment, as shown in Example 1.

DETAILED DESCRIPTION

Before the present invention is described in further detail, it is to be understood that the invention is not limited to the particular embodiments described. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. The scope of the present invention will be limited only by the claims. As used herein, the singular forms “a”, “an”, and “the” include plural embodiments unless the context clearly dictates otherwise.

Specific structures, devices, and methods relating to improved ultrasound treatment efficiency and operation are disclosed. It should be apparent to those skilled in the art that many additional modifications beside those already described are possible without departing from the inventive concepts. In interpreting this disclosure, all terms should be interpreted in the broadest possible manner consistent with the context. Variations of the term “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, so the referenced elements, components, or steps may be combined with other elements, components, or steps that are not expressly referenced. Embodiments referenced as “comprising” certain elements are also contemplated as “consisting essentially of” and “consisting of” those elements.

This disclosure provides methods and systems for enhancing medicant delivery across the stratum corneum layer of skin and into the epidermis layer. The systems and methods also facilitate movement of the medicant deeper into the epidermis or into the dermis layer and subcutaneous tissue beneath the dermis layer.

The present invention may be described herein in terms of various functional components and processing steps. It should be appreciated that such components and steps may be realized by any number of hardware components configured to perform the specified functions. For example, the present invention may employ various medical treatment devices, visual imaging and display devices, input terminals and the like, which may carry out a variety of functions under the control of one or more control systems or other control devices. In addition, the present invention may be practiced in any number of medical contexts and the exemplary embodiments relating to methods and systems for using acoustic energy to enhance medicant delivery and effectiveness, as described herein, are merely indicative of exemplary applications for the invention. For example, the principles, features and methods discussed may be applied to any medical application, e.g., the methods and systems described herein can be used in combination with any coagulative therapies. Further, various aspects of the present invention may be suitably applied to other applications.

Disclosed is an exemplary method of modulating cells and tissues to enhance medicant delivery and/or effectiveness that comprises delivering energy to a region of interest (ROI) within one or more layers of tissue. In an exemplary embodiment, the energy is acoustic energy (e.g., ultrasound in the range of about 100 kHz to about 500 MHz, more preferably in the range of about 100 kHz to about 20 MHz, and most preferably in the range of about 200 kHz to about 20 MHz). In other exemplary embodiments, the energy is photon based energy (e.g., IPL, LED, laser, white light, etc.), or other energy forms, such radio frequency electric currents, or various combinations of acoustic energy, electromagnetic energy and other energy forms or energy absorbers such as cooling. In yet other exemplary embodiments, combinations of acoustic and photon based energy sources can be used, e.g., pre-treating with photon-based energy and then use of ultrasound energy alone or simultaneously with the photon-based energy, or any other combinations for modulating cells and tissues to enhance medicant delivery and/or effectiveness.

An exemplary method of modulating cells and tissues produces numerous predictable mechanical and thermal physiological effects at a ROI. For example, an exemplary method is predictable in terms of precision and accuracy in targeting and focusing energy at desired three dimensional coordinates within a cell membrane or tissue or a plurality of cell membranes and tissues and at various spatial and temporal energy settings. For example, because cells are on the order of micrometers, and cell membrane thickness is on the order of nanometers, to target an individual cell or membrane would require a very high or extreme frequency, thus a plurality is useful in exemplary embodiments. In an exemplary embodiment ultrasound, photon based or radio frequency (electromagnetic) treatment is provided to artificial or engineered tissues, such as artificial skin or organs, or stem cell derived tissues.

Providing ultrasound energy to cell membranes or tissues can enhance drug delivery and/or effectiveness in numerous ways. For example, the permeability and/or transparency of cell membranes can be modulated. For example, in some embodiments, the permeability and/or transparency of cell membranes is increased. Heating can cause better diffusion of drugs through the layers of skin tissue. Cavitation and radiation force involves sustained oscillatory motion of bubbles (aka stable cavitation) and/or rapid growth and collapse of bubbles (aka inertial cavitation). Resulting fluid velocities, shear forces and shock waves can disrupt cell membranes or tissues and induce chemical changes in the surrounding medium. The collapse of bubbles can additionally increase the bubble core temperature and induce chemical changes in the medium (e.g., generate highly reactive species, such as free radicals). Each of the above effects can impact drug delivery and effectiveness. In addition, other ways to impact drug delivery include melting or mechanically disrupting thermally sensitive or mechanically fragile medicant-carrying liposomes and/or other chemical loaded, gas or liquid filled stabilized spheres, analogous to local delivery.

For example, drug delivery can be enhanced when shock waves generated upon collapse of bubbles disrupt the stratum corneum and thereby enhance skin permeability. Likewise, drug effectiveness can be enhanced when shock waves transiently compromise the integrity of cell membranes or tissues, or when local free-radical concentration enhances medicant toxicity. Moreover, certain medicants can be activated and/or released using energy. In that regard, a medicant encapsulated in a carrier can be released at the site of interest using energy (e.g., acoustic energy). Consider for example, U.S. Pat. No. 6,623,430, entitled “Method and Apparatus for Safely Delivering Medicants to a Region of Tissue Using Imaging, Therapy and Temperature Monitoring Ultrasonic System”, and co-pending U.S. patent application Ser. No. 08/943,728, entitled “Method and Apparatus for Safely Delivering Medicants to a Region of Tissue Using Ultrasound”, both of which are hereby incorporated by reference.

In various exemplary embodiments, the ROI is located within one of the nonviable epidermis (i.e., the stratum corneum), the viable epidermis, the dermis, the subcutaneous connective tissue and fat, and the muscle. Depths may be in the range of about 0 mm to about 60 mm, 80 mm, or 100 mm or more. In accordance with an exemplary embodiment, the ROI is located about 20 mm to about 30 mm below the stratum corneum. Further, while only one ROI is depicted, a plurality of ROI can be treated, and in some embodiments, simultaneously. For example, the ROI may consist of one or more organs or a combination of tissues either superficial or deep within the body.

This method and system is uniquely capable of disrupting cell membranes or tissues and inducing chemical changes in the surrounding medium at either a single or multiple layers of skin tissue simultaneously (e.g., a plurality of depths within a cell membrane or tissue simultaneously). For example, one frequency of acoustic energy at one skin layer might generate shock waves upon collapse of bubbles to disrupt the stratum corneum and thereby enhance skin permeability. A different frequency of acoustic energy at a different skin layer might simply provide heat to cause better diffusion of medicants through the layers of skin tissue. Yet another frequency of acoustic energy at a different skin layer might compromise the integrity of cell membranes or tissues, or generate local free-radicals to enhance or reduce medicant toxicity. In an exemplary embodiment, acoustic energy is deposited in three-dimensions and at variable depths to selectively increase tissue permeability to thereby steer or guide the medicant through the tissue to a region of interest.

For example, and with reference to FIG. 1A, an exemplary embodiment provides a method 100 for enhancing medicant delivery and/or effectiveness comprising the steps of: providing a source of acoustic energy 102; presenting a medicant to a cell membrane or tissue 104; and focusing the acoustic energy from the source to a plurality of depths within the cell membrane or tissue 106, wherein the acoustic energy is in the range of about 100 kHz to about 500 MHz, wherein the plurality of depths are each in the range of about 0 mm to about 100 mm; and wherein the delivery and/or effectiveness of the medicant is enhanced 108.

Yet another exemplary embodiment provides a method for delivering a medicant to a region of interest within a cell membrane or tissue comprising the steps of: providing a source of acoustic energy; presenting a medicant to the cell membrane or tissue; focusing the acoustic energy from the source to a first depth within the cell membrane or tissue, wherein the acoustic energy has a first spatial and temporal energy profile; and focusing the acoustic energy from the source to a second depth within the cell membrane or tissue, wherein the acoustic energy has a second spatial and temporal energy profile; and wherein the medicant is delivered to the region of interest.

Medicants can be first introduced to a region of interest orally, by diffusion upon application to the skin, circulation following entry into the circulatory system, direct injection thereto, to name a few. That said, introduction may occur either in or not in direct contact with the circulatory system. For example, in some exemplary embodiments, the methods and systems disclosed herein affect chemicals naturally occurring or already existing within the body (e.g., cells, amino acids, proteins, antibodies, minerals, vitamins, etc.) in terms of, for example, concentration, function, and cell division properties. In one exemplary embodiment, the method and system disclosed herein “spur” or catalyze cellular processes, for example cell growth.

In accordance with exemplary embodiments, a coupling agent, comprised of at least one of a gel, cream, liquid, emulsion solid, composite or other compound, is used to couple the probe to a patient's body. In an exemplary embodiment, the coupling agent contains medicants that are delivered to the patient's body during the emission of energy from the probe.

In accordance with an aspect of an exemplary embodiment, the medicant is also used to couple a probe to the skin. Therefore, the medicant can have multiple uses. First, the medicant is used to couple the probe to the skin. Second, since the medicant contains drugs and other medicines, the same are delivered to the skin when energy is applied from the probe (e.g, via sonophoresis).

In an exemplary embodiment, the medicines and drugs within the medicant are used for skin treatment. Therefore, as the patient is being treated by the application of energy at non-ablative levels, therapeutic drugs are also being administered to the patient to treat skin disorders.

An exemplary system 14 for modulating cells and tissues to enhance medicant delivery and/or effectiveness is provided and depicted in FIG. 1B. An exemplary system 14 comprises a display or indicator 22, a control system 20, and a probe 18.

Display system can be any type of system that conveys images or information apart from images about system 14 or ROI 12 to the user. Therefore, display system 22 can be a computer monitor, television screen or it can be a simply type of indicator system such a liquid crystal display or light emitting diode display in various exemplary embodiments. Liquid crystal displays and light emitting diode displays are particularly useful when system 14 is a hand-held system.

In accordance with another exemplary embodiment, with reference to FIG. 2, an exemplary treatment system 1200 can be configured with and/or combined with various auxiliary systems to provide additional functions. For example, an exemplary treatment system 1200 for treating a region of interest 1206 can comprise a control system 1202, a probe 1204, and a display 1208. Treatment system 1200 further comprises one or more of an auxiliary imaging modality 1274 and/or one or more of an auxiliary monitoring or sensing modality 1272, which may be based upon at least one of photography and other visual optical methods, magnetic resonance imaging (MRI), computed tomography (CT), optical coherence tomography (OCT), electromagnetic, microwave, or radio frequency (RF) methods, positron emission tomography (PET), infrared, ultrasound, acoustic, or any other suitable method of visualization, localization, or monitoring within region-of-interest 1206, including imaging/monitoring enhancements. Such imaging/monitoring enhancement for ultrasound imaging via probe 1204 and control system 1202 could comprise M-mode, persistence, filtering, color, Doppler, and harmonic imaging among others; furthermore an ultrasound treatment system 1270, as a primary source of treatment, may be combined with a secondary source of treatment 1276, including radio frequency (RF) energy, microwave energy, or other photon based energy methods including intense pulsed light (IPL), laser, infrared laser, microwave, or any other suitable energy source. A multi-modality coupler analogous to FIG. 1B is a particularly useful embodiment for a multi-modality treatment, sensing, monitoring and imaging system.

In an exemplary embodiment, with reference to FIG. 3, an exemplary system 16, comprising a display 22, a control system 20, a transducer 19, is used to deliver energy 2, 4, 6, and/or 8 to and monitor ROI 12, within one or more of stratum corneum 85, viable epidermis 86, dermis 88, subcutaneous connective tissue and fat 82, and muscle 84. Other exemplary systems are disclosed in co-pending U.S. patent application Ser. No. 10/950,112 entitled “Method and System For Combined Ultrasound Treatment”, which is hereby incorporated by reference.

With continued reference to FIG. 3, an exemplary transducer 19 is a transducer that delivers ultrasound energy 2, 4, 6 and/or 8 to ROI 12. In some embodiments, a fluid filled or gel couple is used to couple transducer 19 to a patient's body. In some embodiments, an additional coupling is necessary and/or multiple fluid filled or gel couples are used, each having distinct acoustic properties.

In another exemplary embodiment, suction is used to attach transducer 19 to the patient's body. In this exemplary embodiment, a negative pressure differential is created and transducer 19 attaches to stratum corneum 85 by suction. A vacuum-type device is used to create the suction and the vacuum device can be integral with, detachable, or completely separate from transducer 19. The suction attachment of transducer 19 to stratum corneum 85 and associated negative pressure differential ensures that transducer 19 is properly coupled to stratum corneum 85. Further, the suction-attachment also reduces the thickness of the tissue to make it easier to reach distinct layers of tissue.

With additional reference to FIG. 3, ultrasound energy 2, 4, 6 and/or 8 can be emitted in various energy fields. Energy fields can be focused, unfocused, defocused, and/or made substantially planar by transducer 19 to provide a plurality of different effects. Energy can be applied at one or more points in one or more C-planes or C-scans by automated or manual movement. For example, a substantially planar energy field can provide a therapeutic and/or pretreatment effect, a focused energy field can provide a more intense therapeutic effect, and a non-focused energy field can provide a more mild therapeutic effect. It should be noted that the term “non-focused” as used throughout, is meant to encompass energy that is unfocused or defocused.

An exemplary transducer 19 emits ultrasound energy for imaging, or treatment, or a combination of both imaging and treatment. In an exemplary embodiment, transducer 19 is configured to emit ultrasound energy at specific depths in ROI 12, as described below. In this exemplary embodiment of FIG. 3, transducer 19 emits unfocused or defocused ultrasound energy over a wide area in ROI 12 for treatment purposes.

With reference to FIGS. 4A and 4B, transducer 19 can comprise one or more transducers configured for facilitating treatment. Transducer 19 can also comprise one or more transduction elements, e.g., elements 26A or 26B. The transduction elements can comprise a piezoelectrically active material, such as lead zirconante titanate (PZT), or any other piezoelectrically active material, such as a piezoelectric ceramic, crystal, plastic, and/or composite material, as well as lithium niobate, lead titanate, barium titanate, and/or lead metaniobate. In addition to, or instead of a piezoelectrically active material, transducer 19 can comprise any other materials configured for generating radiation and/or acoustical energy. Transducer 19 can also comprise one or more matching and/or backing layers configured along with the transduction elements such as coupled to the piezoelectrically active material. Transducer 19 can also be configured with single or multiple damping elements along the transduction elements.

In accordance with an exemplary embodiment, the thickness of the transduction elements of transducer 19 can be configured to be uniform. That is, the transduction elements can be configured to have a thickness that is substantially the same throughout. In accordance with another exemplary embodiment, the transduction elements can also be configured with a variable thickness, and/or as a multiple damped device. For example, the transduction elements of transducer 19 can be configured to have a first thickness selected to provide a center operating frequency of a lower range, for example from approximately 1 kHz to 3 MHz. Transduction element 26 can be configured with a second thickness selected to provide a center operating frequency of a higher range, for example from approximately 3 to 100 MHz, or more.

Transducer 19 can be configured as a single broadband transducer excited with at least two or more frequencies to provide an adequate output for raising the temperature within ROI 12 to a desired level. Transducer 19 can also be configured as two or more individual transducers, wherein each transducer 19 comprises transduction elements, the thickness of which may be selected as above to provide a desired center operating frequency.

Moreover, in an exemplary embodiment, any variety of mechanical lenses or variable focus lenses, e.g. liquid-filled lenses, may also be used to additionally focus and or defocus the energy field. For example, with reference to exemplary embodiments depicted in FIGS. 4A and 4B, transducer 19 may also be configured with an electronic focusing array 24 in combination with one or more transduction elements to facilitate increased flexibility in treating ROI 12. Array 24 may be configured in a manner similar to transducer 19. That is, array 24 can be configured as an array of electronic apertures that may be operated by a variety of phases via variable electronic time delays, for example, T_(i) . . . T_(j). By the term “operated,” the electronic apertures of array 24 may be manipulated, driven, used, and/or configured to produce and/or deliver energy in a manner corresponding to the phase variation caused by electronic time delays. For example, these phase variations can be used to deliver defocused beams, planar beams, and/or focused beams, each of which may be used in combination to achieve different physiological effects in ROI 12.

Transduction elements may be configured to be concave, convex, and/or planar. For example, in an exemplary embodiment depicted in FIG. 4A, transduction elements 26A and 26B are configured to be concave in order to provide focused energy for treatment of ROI 12. Additional embodiments are disclosed in U.S. patent application Ser. No. 10/944,500, entitled “System and Method for Variable Depth Ultrasound Treatment”, incorporated herein by reference. In an exemplary embodiment of FIG. 4A transduction elements 24 and associated time or phase delays are perpendicular to that shown in FIG. 4A, whereby such perpendicularly disposed transduction elements 24 are therapy, imaging, or dual-mode imaging-therapy elements.

In another exemplary embodiment, depicted in FIG. 4B, transduction elements 26A and 26B can be configured to be substantially flat in order to provide substantially uniform energy to ROI 12. In an exemplary embodiment of FIG. 4B transduction elements 24 and associated time or phase delays are perpendicular to that shown in FIG. 4B, whereby such perpendicularly disposed transduction elements 24 are therapy, imaging, or dual-mode imaging-therapy elements. While FIGS. 4A and 4B depict exemplary embodiments with the transduction elements configured as concave and substantially flat, respectively, the transduction elements can be configured to be concave, convex, and/or substantially flat. In addition, the transduction elements can be configured to be any combination of concave, convex, and/or substantially flat structures. For example, a first transduction element can be configured to be concave, while a second transduction element within transducer 19 can be configured to be substantially flat.

With reference to FIGS. 4C and 4D, transducer 19 can also be configured as an annular array to provide planar, focused and/or non-focused acoustical energy. For example, in accordance with an exemplary embodiment, an annular array 28 can comprise a plurality of rings 30, 32, 34 to N. Rings 30, 32, 34 to N can be mechanically and electrically isolated into a set of individual elements, and can create planar, focused, or non-focused waves. For example, such waves can be centered on-axis, such as by methods of adjusting corresponding transmit and/or receive delays, T₁, T₂, T₃ . . . T_(N). An electronic focus can be suitably moved along various depth positions, and can enable variable strength or beam tightness, while an electronic defocus can have varying amounts of defocusing. In accordance with an exemplary embodiment, a lens and/or concave, convex, and/or substantially flat shaped annular array 28 can also be provided to aid focusing or defocusing such that any time differential delays can be reduced. Movement of annular array 28 in one, two or three-dimensions, or along any path, such as through use of probes and/or any conventional robotic arm mechanisms, may be implemented to scan and/or treat a volume or any corresponding space within ROI 12.

With reference to FIG. 4E, an exemplary transducer 570 can also be configured as a spherically focused single element 572, annular/multi-element 574, annular array with imaging region(s) 576, line focused single element 578, 1-D linear array 580, 1-D curved (convex/concave) linear array 582, and/or 2-D array 584, with mechanical focus 585, convex lens focus 586, concave lens focus 587, compound/multiple lens focus 588, and/or planar array form 589, to achieve focused, unfocused, or non-focused sound fields for both imaging and/or therapy. Other lens shapes can still be used in other exemplary embodiments of the present invention. Analogous to spherically focused single element 572 to be configured for multiple annulii 574 and/or imaging regions 576, an exemplary embodiment for the therapeutic line-focused single element 578, and 1-D and 2-D arrays 580, 582 and 584 is to dispose one or more imaging elements or imaging arrays in their aperture, such as along the center of their aperture. In general a combination of imaging and therapy transducers or dual mode imaging-therapy transducers can be utilized.

An exemplary transducer is suitably controlled and operated in various manners by control system 20. In an exemplary embodiment depicted in FIGS. 5A-5C, control system 20 is configured for coordination and control of the entire acoustic energy system. For example, control system 20 can suitably comprise power source components 36, sensing and monitoring components 38, cooling and coupling controls 40, and/or processing and control logic components 42. Control system 20 can be configured and optimized in a variety of ways with more or less subsystems and components to enhance therapy, imaging and/or monitoring, and the embodiments in FIGS. 5A and 5B are merely for illustration purposes.

For example, for power sourcing components 36, control system 20 can comprise one or more direct current (DC) power supplies 44 configured to provide electrical energy for entire control system 20, including power required by a transducer electronic amplifier/driver 48. A DC current sense device 46 can also be provided to confirm the level of power going into amplifiers/drivers 48 for safety and monitoring purposes.

Amplifiers/drivers 48 can comprise multi-channel or single channel power amplifiers and/or drivers. In accordance with an exemplary embodiment for transducer array configurations, amplifiers/drivers 48 can also be configured with a beamformer to facilitate array focusing. An exemplary beamformer can be electrically excited by a digitally controlled waveform synthesizer/oscillator 50 with related switching logic.

Power sourcing components 36 can also include various filtering configurations 52. For example, switchable harmonic filters and/or matching may be used at the output of amplifier/driver/beamformer 48 to increase the drive efficiency and effectiveness. Power detection components 54 may also be included to confirm appropriate operation and calibration. For example, electric power and other power detection components 54 may be used to monitor the amount of power going to probe 18.

Various sensing and monitoring components 38 may also be suitably implemented within control system 20. For example, in accordance with an exemplary embodiment, monitoring, sensing, interface and control components 56 may be configured to operate with various motion detection systems implemented within transducer 19 to receive and process information such as acoustic or other spatial and/or temporal information from ROI 12. Sensing and monitoring components 38 can also include various controls, interfacing and switches 58 and/or power detectors 54. Such sensing and monitoring components 38 can facilitate open-loop and/or closed-loop feedback systems within treatment system 14.

In an exemplary embodiment, sensing and monitoring components 38 comprise a sensor that is connected to an audio or visual alarm system to prevent overuse of system 14. In this exemplary embodiment, the sensor senses the amount of energy transferred to stratum corneum 85, viable epidermis 86, viable dermis 88, subcutaneous connective tissue and fat 82, or muscle 84, or the time that system 14 has be actively emitting energy. When a certain time or temperature threshold has been reached, the alarm sounds an audible alarm or causes a visual indicator to activate to alert the user that the threshold is reached. This prevents the user from overusing system 14. In an exemplary embodiment, the sensor could be operatively connected to control system 20 and force control system 20 to stop emitting ultrasound energy 2, 4, 6 and/or 8 from probe 18.

A cooling/coupling control system 60 may be provided to remove waste heat from an exemplary probe 18, provide a controlled temperature at the superficial tissue interface and deeper into tissue, and/or provide acoustic coupling from probe 18 to ROI 12. Such cooling/coupling control system 60 can also be configured to operate in both open-loop and/or closed-loop feedback arrangements with various coupling and feedback components.

Additionally, an exemplary control system 20 can further comprise various system processors and digital control logic 62, such as one or more controls or interfacing switches 58 and associated components, including firmware and software 64, which interfaces to user controls and interfacing circuits as well as input/output circuits and systems for communications, displays, interfacing, storage, documentation, and other useful functions. Software 64 controls all initialization, timing, level setting, monitoring, safety monitoring, and all other system functions required to accomplish user-defined treatment objectives. Further, various mechanisms 66 can also be suitably configured to control operation.

With reference to FIG. 5C, an exemplary transducer is suitably controlled and operated in various manners by a hand-held format control system 1000. An external battery charger 1002 can be used with rechargeable-type batteries 1004 or batteries 1004 can be single-use disposable types, such as AA-sized cells. Power converters 1006 produce voltages suitable for powering a driver/feedback circuit 1008 with tuning network 1010 driving a transducer 1012 coupled to the patient via one or more fluid filled or gel couples. In some embodiments, a fluid filled or gel couple is coupled to the patient with an acoustic coupling agent 1015. In addition, a microcontroller and timing circuits 1016 with associated software and algorithms provide control and user interfacing via a display 1018, oscillator 1020, and other input/output controls 1022 such as switches and audio devices. A storage element 1024, such as an EEPROM, secure EEPROM, tamper-proof EEPROM, or similar device holds calibration and usage data. A motion mechanism with feedback 1026 can be suitably controlled to scan the transducer, if desirable, in a line or two-dimensional pattern and/or with variable depth. Other feedback controls include a capacitive, acoustic, or other coupling detection means and/or limiting controls 1028 and thermal sensor 1030. A combination of the secure EEPROM with at least one of a fluid filled or gel couple, transducer 1012, thermal sensor 1030, coupling detectors 1028, or tuning network 1010 along with a plastic or other housing can comprise a disposable tip 1032.

With reference again to FIG. 3, an exemplary system 14 also includes display system 22 to provide images of the ROI 12 in certain exemplary embodiments wherein ultrasound energy is emitted from transducer 19 in a manner suitable for imaging. Display system can be any type of system that conveys images or information apart from images about system 14 or ROI 12 to the user. Therefore, display system 22 can be a computer monitor, television screen or it can be a simply type of indicator system such a liquid crystal display or light emitting diode display in various exemplary embodiments. Liquid crystal displays and light emitting diode displays are particularly useful when system 14 is a hand-held system.

Display system 22 enables the user to facilitate localization of the treatment area and surrounding structures, e.g., identification of cell membranes or tissues. After localization, delivery of ultrasound energy 2, 4, 6 and/or 8 at a depth, distribution, timing, and energy level is provided, to achieve the desired therapy, imaging and/or monitoring. Before, during, and/or after therapy, i.e., before, during and/or after delivery of ultrasound energy, monitoring of the treatment area and surrounding structures can be conducted to further plan and assess the results and/or provide feedback to control system 20 and a system operator via display system 22. In accordance with an exemplary embodiment, localization can be facilitated through ultrasound imaging that can be used to define an ROI 12 within one or more layers of skin tissue.

For ultrasound energy delivery, transducer 19 can be mechanically and/or electronically scanned to place treatment zones over an extended area in ROI 12. A treatment depth can be adjusted between a range of approximately 1 to 100 millimeters, and/or the greatest depth of muscle 84. Such delivery of energy can occur through imaging of the targeted cell membrane or tissue and then applying ultrasound energy, or application of ultrasound energy at known depths over an extended area without initial or ongoing imaging.

The ultrasound beam from transducer 19 can be spatially and/or temporally controlled by changing the spatial parameters of transducer 19, such as the placement, distance, treatment depth and transducer 19 structure, as well as by changing the temporal parameters of transducer 19, such as the frequency, drive amplitude, and timing, with such control handled via control system 20. Such spatial and temporal parameters can also be suitably monitored and/or utilized in open-loop and/or closed-loop feedback systems within ultrasound system 16.

In accordance with another exemplary embodiment of the present invention, with reference again to FIG. 3, an exemplary monitoring method may comprise monitoring the temperature profile or other tissue parameters of ROI 12, such as attenuation, speed of sound, or mechanical properties such as stiffness and strain of the treatment region and suitably adjust the spatial and/or temporal characteristics and energy levels of ultrasound energy 2, 4, 6 and/or 8 emitted from transducer 19. The results of such monitoring techniques may be indicated on display system 22 by means of one-, two-, or three-dimensional images of monitoring results, or may simply comprise a success or fail-type indicator, or combinations thereof. Additional treatment monitoring techniques may be based on one or more of temperature, video, profilometry, and/or stiffness or strain gauges or any other suitable sensing technique.

Any amount of energy can be used as long as the tissue within ROI 12 is not ablated or coagulated. In an exemplary embodiment, the energy emitted from probe 18 is unfocused or defocused ultrasound energy 2, 4, 6 and/or 8. Alternatively, focused ultrasound energy 2, 4, 6 and/or 8 could be emitted from probe 18 and applied to ROI 12.

In certain exemplary embodiments, system 14 is equipped with certain features to aid the user. One feature is a disposable tip that covers probe 18 during use. The disposable tip enables ultrasound energy 2, 4, 6, and/or 8 to pass through the tip and contact the patient. But, the disposable tip can be removed from probe 18 after use and replaced with a new disposable tip to prevent the spread of germs from one patient to another that might reside on probe 18 after contact with a patient's stratum corneum 85. Different size disposable tips can be used and fall within the scope of the present invention.

In one exemplary embodiment, the energy released into ROI 12 increases the local temperature within ROI 12 from approximately 1°-25° C. over a body's normal temperature. Therefore the temperature within ROI 12 during treatment is between approximately 35°-60° C. In another exemplary embodiment, the temperature is raised approximately 1°-15° C. over a body's normal temperature. Therefore, in this embodiment, the temperature within ROI 12 is between approximately 35°-49° C. While specific temperature ranges are disclosed herein, it should be noted that any temperature is considered to fall within the scope of the present invention.

In certain embodiments, the temperature increase may be very high but applied for a short enough time period so that the energy delivered to ROI 12 does not cause tissue ablation or coagulation. In other situations, the temperature increase may be fairly small and applied long enough to have an effect without causing tissue ablation or coagulation.

The time-temperature profile can be modeled and optimized with the aid of the thermal dose concept. The thermal dose, or t₄₃, is the exposure time at 43° C. which causes an equivalent biological effect due to an arbitrary time-temperature heating profile. Typically an ablative lesion forms on the order of one second at 56° C., which corresponds to a thermal dose of one hundred and twenty minutes at 43° C. The same thermal dose corresponds to 50° C. for approximately one minute. Thus a non-ablative profile can contain high temperatures for very short times and/or lower temperatures for longer times or a combination of various time-temperature profiles. For example, temperatures as high as 56° C. for under one second or 46° C. for under fifteen minutes can be utilized. Such processes can be implemented in various exemplary embodiments, whereby one or more profiles may be combined into a single treatment.

In an exemplary embodiment the temperature at ROI 12 is raised to a high level, such as approximately 50° C. or more and held for several seconds. In another exemplary embodiment, the temperature is raised to a high level, (for example greater than 50° C.), for under one second up to five seconds or more, and then turned off for under one second up to five seconds or more, and repeated to create a pulsed profile.

In another exemplary embodiment, the temperature is raised quickly to a high level (greater than 50° C.), and then dropped to a lower temperature (less than 50° C.), and then maintained at that temperature for a given time period such as one second up to several seconds or over a minute.

In another exemplary embodiment, the temperature is increased quickly to a high level (THIGH), whereby THIGH is greater than 40° C., and the power to system 14 is turned off, but turned on again once the temperature drops below a lower threshold, (T_(LOW)), whereby T_(LOW) is less than T_(HIGH). Once the temperature reaches T_(HIGH) again power to system 14 is turned back off and this process is repeated, in effect acting like a thermostat. The process is terminated after a total treatment time of under one second to one minute or more.

In another exemplary embodiment, the temperature is raised quickly to a high level (T_(START)), whereby T_(START) is greater than 40° C. and then turned off, but turned on again before the temperature drops appreciably (i.e. by a few degrees) below T_(START), whereby the temperature may then increase a small amount (i.e. by a few degrees) over T_(START) before the power is turned off again. In such an exemplary embodiment the temperature quickly reaches a starting point and then may be allowed to increase to a higher temperature yet still remain in a non-ablative or coagulative regime before the treatment is ended.

The present invention may be described herein in terms of various functional components and processing steps. It should be appreciated that such components and steps may be realized by any number of hardware components configured to perform the specified functions. For example, the present invention may employ various medical treatment devices, visual imaging and display devices, input terminals and the like, which may carry out a variety of functions under the control of one or more control systems or other control devices. In addition, the present invention may be practiced in any number of medical contexts and that the exemplary embodiments relating to a system as described herein are merely indicative of exemplary applications for the invention. For example, the principles, features and methods discussed may be applied to any medical application. Further, various aspects of the present invention may be suitably applied to other applications, such as other medical or industrial applications.

As will be described with respect to FIGS. 6A, 6B, 6C, and 6D, an ultrasound assisted drug delivery probe 2010 can be positioned atop and coupled to a skin surface 2012. The skin surface 2012 can be located above a stratum corneum 2014, an epidermis 2016, and a dermis 2018. A region of interest 2020 can be any contiguous location within the illustrated skin surface 2012, the stratum corneum 2014, the epidermis 2016, the dermis 2018, or a combination thereof. The region of interest 2020 can be a region of interest as described herein. The ultrasound assisted drug delivery probe 2010 can include an ultrasound source 2022, which can include one or more transducers 2024. The ultrasound source 2022 can be any source described herein. The transducers 2024 can be any transducers described herein. The one or more transducers 2024 can each independently be a single transduction element, an array of transduction elements, or a group of arrays of transduction elements. The ultrasound assisted drug delivery probe 2010 can be coupled to a power supply 2026 and electronics 2028 sufficient for the operation of an ultrasound system. The power supply 2026 can be any power supply known to one of skill in the art to be suitable for powering an ultrasound probe, such as any power supply described herein, among others. The electronics 2028 can be any electronics known to one of skill in the art to be suitable for operating an ultrasound probe, such as any electronics described herein, among others. The ultrasound assisted drug delivery probe 2010 can be coupled to a control module 2030 adapted to control the emission of ultrasound from the ultrasound assisted drug delivery probe 2010. The control module 2030 can be any control module or controller known to one of skill in the art to be suitable for controlling the emission characteristics of an ultrasound probe, such as any control module or controller described herein, among others.

Referring to FIG. 6A, the ultrasound assisted drug delivery probe 2010 can be coupled to the skin surface 2012 by way of a coupling medium 2032. The coupling medium 2032 can include a medicant 2034.

Referring to FIG. 6B, the arrangement illustrated in FIG. 6A is illustrated after the ultrasound assisted drug delivery probe 2010 has begun emitting a first acoustic energy field 2036 that penetrates at least through the skin surface 2012 and the stratum corneum 2014 and penetrates at least partially into the epidermis 2016. In response to the first acoustic energy field 2036, the medicant 2034 can be driven from above the skin surface 2012 through the skin surface 2012, into or through the stratum corneum 2014, and into the epidermis 2016.

It should be appreciated that there exist intermediate states between the state of the arrangement illustrated in FIG. 6A and that illustrated in FIG. 6B, where the first acoustic energy field 2036 penetrates only partially into the stratum corneum 2014, or penetrates throughout the stratum corneum 2014 but not into the epidermis 2016, or penetrates throughout the stratum corneum 2014 and partially into the epidermis 2016 to a depth different than that illustrated. In similar intermediate states, the medicant 2034 can penetrate only partially into the stratum corneum 2014, or penetrates throughout the stratum corneum 2014 but not into the epidermis 2016, or penetrates throughout the stratum corneum 2014 and partially into the epidermis 2016 to a depth different than that illustrated.

Referring to FIG. 6C, the arrangement illustrated in FIGS. 6A and 6B is illustrated after the ultrasound assisted drug delivery probe 2010 has begun emitting a second acoustic energy field 2038 that penetrates at least through the skin surface 2012, the stratum corneum 2014, and the epidermis 2016, and penetrates at least partially into the dermis 2018. In response to the second acoustic energy field 2038, the medicant 2034 can be driven from the epidermis 2016 to a deeper portion of the epidermis 2016 or into the dermis 2018.

It should be appreciated that there exist intermediate states between the state of the arrangement in FIG. 6B and that illustrated in FIG. 6C, where the second acoustic energy field 2038 can penetrate throughout the epidermis 2016 but not into the dermis 2018, or can penetrate through the epidermis 2016 and partially into the dermis 2018, or can penetrate into the dermis 2018 to a depth different than that illustrated. In similar intermediate states, the medicant 2034 can penetrate throughout the epidermis 2016 but not into the dermis 2018, or can penetrate through the epidermis 2016 and partially into the dermis 2018, or can penetrate into the dermis 2018 to a depth different than that illustrated.

Referring to FIG. 6D, the arrangement illustrated in FIGS. 6A, 6B, and 6C is illustrated after the medicant 2034 has been driven into the dermis 2018. In the dermis 2018, the medicant 2034 can interact with tissue or enter the blood stream via capillaries. In certain applications, a third acoustic energy field 2040, optionally referred to as a therapeutic acoustic energy field 2040, can be directed to a target volume 2042 within the dermis 2018. The target volume 2042 can be located in a portion of the dermis 2018 containing the medicant 2034.

As will be described with respect to FIGS. 7A, 7B, 7C, and 7D, a delivery system 2044 can include an ultrasound assisted drug delivery probe 2010 and a standoff 2046 comprising a medicant 2034. The ultrasound assisted drug delivery probe 2010 can include features described elsewhere herein. The standoff 2046 can include a plurality of pores in a bottom surface 2048, the plurality of pores being in fluid communication with the medicant 2034. The plurality of pores can be of a size and shape that are sufficient to retain the medicant 2034 within the standoff 2046. In certain aspects, the medicant 2034 is retained in the standoff 2046 by virtue of a surface tension of the medicant 2034. In certain aspects, the standoff 2046 can include a gel pack coupled to the ultrasound assisted drug delivery probe 2010. In certain aspects, the standoff 2046 can be rigid or flexible.

Referring to FIG. 7A, the delivery system 2044 is positioned above the skin surface 2012. In FIG. 7B, the arrangement illustrated in FIG. 7A is illustrated after the delivery system 2044 has been coupled to the skin surface 2012. The ultrasound assisted drug delivery probe 2010 can emit a first acoustic energy field 2036 that penetrates at least through the skin surface 2012 and the stratum corneum 2014 and penetrates at least partially into the epidermis 2016. In response to the first acoustic energy field 2036, the medicant 2034 can be driven from above the skin surface 2012 through the skin surface 2012, into or through the stratum corneum 2014, and into the epidermis.

It should be appreciated that there exist intermediate states between the state of the arrangement in FIG. 7A and that illustrated in FIG. 7B, where the first acoustic energy field 2036 can penetrate only partially into the stratum corneum 2014 or can penetrate throughout the stratum corneum 2014 but not into the epidermis 2016, or can penetrate through the stratum corneum 2014 and partially into the epidermis 2016 to a depth different than that illustrated. In similar intermediate states, the medicant 2034 can penetrate only partially into the stratum corneum 2014, or can penetrate throughout the stratum corneum 2014 but not into the epidermis 2016, or can penetrate throughout the stratum corneum 2014 and partially into the epidermis 2016 to a depth different than that illustrated.

Referring to FIG. 7C, the arrangement illustrated in FIGS. 7A and 7B is illustrated after the ultrasound assisted drug delivery probe 2010 has begun emitting a second acoustic energy field 2038 that penetrates at least through the skin surface 2012, the stratum corneum 2014, and the epidermis 2016, and penetrates at least partially into the dermis 2018. In response to the second acoustic energy field 2038, the medicant 2034 can be driven from the epidermis to a deeper portion of the epidermis 2016, partially into the dermis 2018, or entirely into the epidermis.

It should be appreciated that there exist intermediate states between the state of the arrangement in FIG. 7B and that illustrated in FIG. 7C, where the second acoustic energy field 2038 can penetrate throughout the epidermis 2016 but not into the dermis 2018, or can penetrate through the epidermis 2016 and partially into the dermis 2018, or can penetrate into the dermis 2018 to a depth different than that illustrated. In similar intermediate states, the medicant 2034 can penetrate throughout the epidermis 2016 but not into the dermis 2018, or can penetrate through the epidermis 2016 and partially into the dermis 2018, or can penetrate into the dermis 2018 to a depth different than that illustrated.

Referring to FIG. 7D, the arrangement illustrated in FIGS. 7A, 7B, and 7C is illustrated after the medicant 2034 has been driven into the dermis 2018. In the dermis, the medicant 2034 can interact with the tissue or enter the blood stream via capillaries. In certain applications, a third acoustic energy field 2040, optionally referred to as a therapeutic acoustic energy field 2040, can be directed to a target volume 2042 within the dermis 2018. The target volume 2042 can be located in a portion of the dermis 2018 containing the medicant 2034.

In certain aspects, the delivery system 2044 can be configured as a transdermal patch. For example, the delivery system 2044 can be configured for off-the-shelf operation, where the delivery system 2044 include the medicant 2034 in appropriate dosage within the standoff 2046 and a suitable portable power supply, such as battery power, to power the delivery system 2044. After removing any packaging for the delivery system 2044, the delivery system 2044 can be applied to a location by a patient or a user. In certain aspects, the delivery system 2044 can include an adhesive material on the bottom surface 2048 of the standoff 2046 or a patch that extends over the ultrasound assisted drug delivery probe 2010 to facilitate retention of coupling between the probe 2010 and the skin surface 2012.

In certain aspects, the delivery system 2044 can have an on-off switch or a separate on-off device that allows a patient or user to turn the delivery system 2044 on (and subsequently off) when the ultrasound assisted drug delivery probe 2010 is properly located on the skin surface 2012. The delivery system 2044 can utilize at least one ultrasound energy effect to move the medicant 2034 from the standoff 2046 to below the skin surface 2012.

A delivery system 2044 as described herein can have significant advantages over a traditional transdermal patch. For example, the delivery system 2044 can deliver medicants 2034 having a higher molecular weight, for example, medicants 2034 having a molecular weight of at least about 100 Da or at least about 500 Da. As another example, the delivery system 2044 does not rely on mechanical diffusion, so lower doses of the medicant 2034 can be deployed because more of the medicant 2034 reaches areas beneath the skin surface 2012. As yet another example, the delivery system 2044 is not limited to deploying medicants 2034 having an affinity for both lipophilic and hydrophilic phases or medicants 2034 that are non-ionic. In certain aspects, the delivery system 2044 can include a solar panel, which can optionally be no bigger than the area of a patch covering the ultrasound assisted drug delivery probe 2010, to supplement power to the delivery system 2044.

Referring to FIG. 8, multiple devices, including a micro-channel device 2050 comprising a micro-channel creation means 2052, a first ultrasound device 2054, a second ultrasound device 2056, and a third ultrasound device 2058, can be configured individually or as a part of a single system to independently or cooperatively provide delivery of a medicant 2034. The micro-channel device 2050 comprising the micro-channel creation means 2052 is configured to create a micro-channel 2060 through the stratum corneum 2014. The micro-channel creation means 2052 can be any of the systems or methods described herein. For example, the micro-channel creation means 2052 can employ one or more acoustic energy fields, such as described in the description of FIGS. 6A, 6B, 6C, 6D, 7A, 7B, 7C, and 7D. The micro-channel creation means 2052 can also include one or more micro-needles. The micro-channel creation means 2052 can include a photon-based energy field configured to generate micro-channels 2060 in the stratum corneum 2014.

The micro-channel device 2050, the first ultrasound device 2054, the second ultrasound device 2056, and the third ultrasound device 2058 can move from right to left across the illustrated skin surface 2012, either collectively or independently. A coupling medium 2032 can be applied to the skin surface 2012 before or after the micro-channel creation means 2052 has created a micro-channel 2060. If the micro-channel device 2050, the first ultrasound device 2054, the second ultrasound device 2056, and the third ultrasound device 2058 are operating in series, then the coupling medium 2032 is typically applied to the skin surface 2012 after the micro-channel creation means 2052 has created the micro-channel 2060 to avoid loss of the medicant 2034 or contamination of the medicant 2034 by the micro-channel creation means 2052. The micro-channel device 2050, the first ultrasound device 2054, the second ultrasound device 2056, and the third ultrasound device 2058 can be controlled by a control module 2030, either collectively or independently. In certain aspects, the micro-channel device 2050, the first ultrasound device 2054, the second ultrasound device 2056, and the third ultrasound device 2058 can each be housed in individual cylinders or spheres that are configured to roll across the skin surface 2012.

The first ultrasound device 2054 can be configured to direct a fourth acoustic energy field 2062 into the skin surface 2012. The fourth acoustic energy field 2062 can be configured to drive the medicant 2034 through the micro-channel 2060. In certain aspect, the fourth acoustic energy field 2062 can have the properties of the first acoustic energy field 2036, as described herein.

The second ultrasound device 2056 can be configured to direct a fifth acoustic energy field 2064 into the skin surface 2012. The fifth acoustic energy field 2064 can be configured to drive the medicant 2034 through the epidermis 2016 and optionally through the dermis 2018. In certain aspects, the fifth acoustic energy field 2064 can have the properties of the second acoustic energy field 2038, as described herein.

The third ultrasound device 2058 can be configured to direct a sixth acoustic energy field 2066 into the skin surface 2012. The sixth acoustic energy field 2066 can be configured to interact with the medicant 2034 or with tissue containing or proximate to the medicant 2034. In certain aspect, the sixth ultrasound acoustic energy field 2066 can have the properties of the third acoustic energy field 2040, as described herein.

In addition to the first acoustic energy field 2036, the second acoustic energy field 2038, the third acoustic energy field 2040, the fourth acoustic energy field 2062, the fifth acoustic energy field 2064, or the sixth acoustic energy field 2066, the methods described herein can utilize additional acoustic energy fields configured to provide one or more effects described herein.

In certain aspects, a system such as an ultrasound assisted drug delivery probe 2010, a delivery device 2044, a micro-channel device 2050, a first ultrasound device 2040, a second ultrasound device 2056, a third ultrasound device 2058, or any combination thereof can include various components described herein. For example, a system can include a control module 2030. As one non-limiting example, such a control module 2030 can be the control module 20 described above, which can be configured to receive at least one communication and control a distribution of the acoustic energy field transmitted by the ultrasound energy source, such as, for example, an acoustic transducer 2024. The control module 2030 can be configured to receive a treatment start signal and a treatment stop signal. The control module 2030 can be programmed to provide treatment to the ROI 2020 for a desired outcome. The control module 2030 can initiate and run a treatment program (treatment function), which can include the control of spatial parameters and/or temporal parameters of the ultrasound source, to provide programmed distribution of the acoustic energy field in the ROI 2020. The control module 2030 can be configured to receive feedback from one or more sensors and/or detectors, and the control module 2030 can terminate the treatment program based on the feedback.

The control module 2030 can be configured to communicate with the probe 2010 via wireless interface. In some embodiments, the control module 20 can be a wireless device, which has a display and a user interface such as, for example, a keyboard. Examples of a wireless device can include but are not limited to: a personal data assistant (PDA), a cell phone, a smart phone, an iPhone, an iPad, a computer, a laptop, a netbook, a tablet, or any other such device now known or developed in the future. Examples of wireless interface include but are not limited to any wireless interface described herein and any such wireless interface now known or developed in the future. Accordingly, the probe 2010 can comprise any hardware, such as, for example, electronics, antenna, and the like, as well as, any software that may be used to communicate via wireless interface.

The wireless device can be configured to display an image generated by the probe 2010. The wireless device can be configured to control at least a portion of the probe 2010. The wireless device can be configured to store data generated by the probe 2010 and sent to the wireless device.

Various sensing and monitoring components may also be implemented within control module. For example, monitoring, sensing, and interface control components may be capable of operating with the motion detection system implemented within the probe 2010, to receive and process information such as acoustic or other spatial and temporal information from the ROI 2020. Sensing and monitoring components may also comprise various controls, interfacing, and switches and/or power detectors. Such sensing and monitoring components may facilitate open-loop and/or closed-loop feedback systems within the probe 2010.

In some aspects, sensing and monitoring components may further comprise a sensor that may be connected to an audio or visual alarm system to prevent overuse of the probe 2010. The sensor may be capable of sensing the amount of energy transferred to the skin, and/or the time that the probe 2010 has been actively emitting the acoustic energy. When a certain time or temperature threshold has been reached, the alarm may sound an audible alarm, or cause a visual indicator to activate to alert the user that a threshold has been reached. This may prevent overuse of the device. In some embodiments, the sensor may be operatively connected to the control module and force the control module 2030, to stop emitting the acoustic energy from the probe 2010. In some embodiments, the control module 2030 is operable to control the power supply to change an amount of power provided to the acoustic transducer 2024 in the probe 2010.

A position sensor may be located behind a transducer, in front of a transducer, or integrated into a transducer array. The probe 18 may comprise more than one position sensor, such as, for example, a laser position sensor and a motion sensor, or a laser position sensor and a visual device, or a motion sensor and a visual device, or a laser position sensor, a motion sensor, and a visual device. In some embodiments, position sensor may determine a distance between pulses of the acoustic energy to create a plurality of treatment zones which are evenly spaced or disposed in any spatial configuration in 1-D or 2-D patterns. As the probe 18 is moved in direction, the position sensor determines distance, regardless of a speed that the ultrasound source is move, at which a pulse of acoustic energy is to be emitted in to ROI 12.

In some aspects, the system can further comprise a contact sensor operable to determine if the ultrasound source is coupled to the ROI 12. The tissue contact sensor can communicate to the control module 20 whether the ultrasound source is coupled to the ROI 12.

The first acoustic energy field 2036, second acoustic energy field 2038, or third acoustic energy field 2040 can be planar, focused, weakly focused, unfocused, or defocused. The first acoustic energy field 2036, second acoustic energy field 2038, or third acoustic energy field 2040 can have a frequency in the range of about 1 MHz to about 30 MHz, including, but not limited to, a frequency in the range of about 5 MHz to about 15 MHz, from about 2 MHz to about 12 MHz, from about 3 MHz to about 7 MHz, from about 1 MHz to about 7 MHz, from about 2 MHz to about 5 MHz, from about 3 MHz to about 10 MHz, or from about 1 MHz to about 10 MHz, or other combinations of the lower and upper limits of these ranges not explicitly recited. The first acoustic energy field 2036, second acoustic energy field 2038, or third acoustic energy field 2040 can be configured to avoid damaging the cells in the stratum corneum 2014 or the epidermis 2016.

The first acoustic energy field 2036, second acoustic energy field 2038, or third acoustic energy field 2040 can be pulsed and have a delay of from about 1 μs to about 100 seconds between pulses. The first acoustic energy field 2036, second acoustic energy field 2038, or third acoustic energy field 2040 can be continuous wave. In certain aspects, the first acoustic energy field 2036, second acoustic energy field 2038, or third acoustic energy field 2040 can be pulsed and have a pulse repetition rate of one pulse per 10 μs to one pulse per 100 seconds.

In certain applications, such as generating inertial cavitation in the stratum corneum 2014 which can create micro-channels having an intercellular route from the skin surface 2012 to the epidermis 2016, the first acoustic energy field 2036 can have a pulse width in a range from about 33 ns to about 100 s. In these certain applications, the first acoustic energy field 2036 can be pulsed and can have a pulse width in the range of about 1 μs to about 1 second, or in the range of about 0.01 seconds to about 5 seconds. In these certain applications, the first acoustic energy field 2036 can have a peak intensity of greater than 3 W/cm² and less than or equal to about 100 kW/cm² at the skin surface 2012. In certain aspects, the first acoustic energy field 2036 can have a peak intensity of greater than 10 W/cm², greater than 50 W/cm², greater than 100 W/cm², greater than 300 W/cm², greater than 500 W/cm², greater than 1 kW/cm², greater than 3 kW/cm², or greater than 5 kW/cm². The intensity of the first acoustic energy field 2036 can be below a threshold value for creating a shock wave. A person having ordinary skill in the art will appreciate that this threshold value can vary based on material properties and the specific parameters of the ultrasound being used, and can determine this threshold value for specific materials and sets of parameters experimentally or computationally.

In certain applications, such as generating acoustic streaming providing acoustic streaming pressure to the stratum corneum 2014, the epidermis 2016, or a combination thereof, the first acoustic energy field 2036 can be pulsed and the pulses can have a pulse width in a range of about 33 ns to about 100 s, including, but not limited to, a range of about 1 μs to about 10 seconds or a range of about 0.001 seconds to about 5 seconds. In these certain applications, the first acoustic energy field 2036 can have a peak intensity in the range from about 5 W/cm² to about 100 kW/cm² at the skin surface 2012. In certain aspects, the first acoustic energy field 2036 can have a peak intensity of greater than 10 W/cm², greater than 50 W/cm², greater than 100 W/cm², greater than 300 W/cm², greater than 500 W/cm², greater than 1 kW/cm², greater than 3 kW/cm², or greater than 5 kW/cm². Acoustic streaming can generate micro-channels having a transcellular route from the skin surface 2012 to the epidermis 2016. In these certain applications, acoustic streaming generated by the first acoustic energy field 2036 can create pressures ranging from about 10 kPa to about 120 MPa, including, but not limited to, pressures ranging from about 10 kPa to about 10 MPa and pressures ranging from about 10 MPa to about 120 MPa, in the stratum corneum 2014, the epidermis 2016, or a combination thereof.

In certain applications, such as generating inertial cavitation in the stratum corneum 2014 and acoustic streaming providing acoustic streaming pressure to the stratum corneum 2014, the epidermis 2016, or a combination thereof, which can generate micro-channels having both an intercellular route and a transcellular route from the skin surface 2012 to the epidermis 2016, the first acoustic energy 2036 can provide two or more effects, such as inertial cavitation and acoustic streaming, simultaneously or alternating. In certain aspects, generating inertial cavitation and acoustic streaming can facilitate moving a larger medicant, such as a medicant with a molecular weight greater than 500 Da, through the stratum corneum 2014.

In certain applications, the second acoustic energy 2038 can be configured to generate inertial cavitation or acoustic streaming in the epidermis 2016, the dermis 2018, or a combination thereof. In certain aspects, the second acoustic energy 2038 can be configured to increase diffusion of the medicant 2034 through the epidermis 2016 and the dermis 2018. In certain aspects, the second acoustic energy 2038 can provide a pressure in a range from about 100 kPa to about 100 MPa to push the medicant 2034 through the epidermis 2016 and into the dermis 2018.

It should be appreciated that the effects described herein are tissue-dependent, so the ultrasound energy necessary to generate inertial cavitation or acoustic streaming in one type of tissue might be different than the ultrasound energy necessary to generate inertial cavitation or acoustic streaming in a different type of tissue. It should also be appreciated that for a certain effect to be generated, the threshold for generating that effect must be exceeded. However, the thresholds for generating the effects described herein, such as inertial cavitation and subsequent acoustic streaming, in tissues are generally unknown.

With respect to inertial cavitation, aside from a single experimental study regarding the frequency-dependence of the threshold for inertial cavitation in canine skeletal muscle, a recent article by Church et al. states that “too little information on the experimental threshold for inertial cavitation in other tissues is available” to make conclusions regarding frequency-dependent trends. See, Church C C, et al. “Inertial cavitation from ARFI imaging and the MI”, Ultrasound in Med. & Biol., Vol. 41, No. 2, pp. 472-485 (2015). This observation is solely about the inertial cavitation threshold as it relates to frequency, and does not take into account the other spatial and temporal parameters aside from frequency. Accordingly, one of skill in the art should appreciate that the present invention is disclosed in terms of effects that have been shown to produce a specific result, i.e., transporting a medicant across the stratum corneum, and a set of general parameters that are suitable for achieving that result are set forth above. One of skill in the art should also appreciate that the presence of inertial cavitation can be identified by a characteristic broadband signal that is the result of the complex dynamics associated with inertial cavitation.

With respect to acoustic streaming, this effect can be generated by an effect including the aforementioned inertial cavitation or without the inertial cavitation. In instances without the inertial cavitation, acoustic streaming can be accomplished by introducing heat into a tissue, for example the stratum corneum, which expands the tissue, then applying a pressure to the medicant or a carrier containing the medicant to initiate acoustic streaming.

The inertial cavitation and acoustic streaming effects are described herein with respect to the discrete layers of the skin, but can penetrate to a greater depth beneath the skin surface to enhance the penetration of the medicant deeper into the skin or into subcutaneous tissue.

In certain aspects, the first acoustic energy 2036 and the second acoustic energy 2038 can be substantially the same. In certain aspects, the second acoustic energy 2038 can have a frequency that concentrates the acoustic energy deeper and moves the medicant 2034 into the dermis 2018. In certain aspects, the second acoustic energy 2038 can be configured to cause a thermal effect in the epidermis 2016 or the dermis 2018, which is non-destructive to the cells of the epidermis 2016 or dermis 2018.

The first acoustic energy 2036, second acoustic energy 2038, or third acoustic energy 2040 can be generated from one or more ultrasound sources.

In certain aspects, the ultrasound assisted drug delivery probe 2010 can be configured to create an intensity gain from the ultrasound assisted drug delivery probe 2010 to the target volume 2042 of at least about 5, including, but not limited to, an intensity gain of at least about 10, at least about 25, at least about 50, or at least about 100. In aspects having a focused or a strongly focused ultrasound, the ultrasound assisted drug delivery probe 2010 can be configured to create an intensity gain from the ultrasound assisted drug delivery probe 2010 to the target volume 2042 of at least about 50, including, but not limited to, an intensity gain of at least about 100, or at least about 500. In aspects having a weakly focused ultrasound, the ultrasound assisted drug delivery probe 2010 can be configured to create an intensity gain from the ultrasound assisted drug delivery probe 2010 to the target volume 2042 of at least about 5.

In certain aspects with pulsed ultrasound, a first pulse can be ultrasound having a first type of focus, a second pulse can be ultrasound having a second type of focus, a third pulse can be ultrasound having the first type of focus or a third type of focus, and so on. Any combination of focused, defocused, or unfocused energy can be used for any of the various pulses.

In certain aspects, the first acoustic energy 2036, second acoustic energy 2038, or third acoustic energy 2040 can create a thermal effect, a mechanical effect, or a combination thereof in the target volume 2042. A mechanical effect is a non-thermal effect within a medium that is created by acoustic energy. A mechanical effect can be one of, for example, acoustic resonance, acoustic streaming, disruptive acoustic pressure, shock waves, inertial cavitation, and non-inertial cavitation.

Referring to FIG. 9, a flowchart illustrating a method 2200 of ultrasound assisted drug delivery is provided. At process block 2202, the method 2200 can include administering a medicant 2034 to a skin surface 2012. At process block 2203, the method 2200 can include creating micro-channels 2060 through the stratum corneum 2014. At process block 2204, the method 2200 can include applying a first acoustic energy field 2036 to direct the medicant 2034 through the microchannels 2060. At process block 2206, the method 2200 can include applying a second acoustic energy field 2038 to direct the medicant 2034 through the epidermis 2016 and into the dermis 2018. At process block 2208, the method 2200 can include moving the medicant 2034 into a target volume 2042 to interact with tissue, be transported via blood vessels, or a combination thereof. At process block 2210, the method 2200 can include monitoring the medicant 2034 effect. At decision block 2218, the method 2200 can include determining whether the treatment is complete. If the treatment is determined to be complete by answering yes 2222 to decision block 2218, then the method 2200 can be completed. If the treatment is determined to be incomplete by answering no 2220 to decision block 2218, then the method 2200 can return to process block 2202 or can proceed to optional process block 2212.

At optional process block 2212, the method 2200 can include directing a therapeutic acoustic energy field 2040 into the target volume 2042. When the medicant is located in or near the target volume 2042, at optional process block 2214, the method 2200 can include directing a third acoustic energy field 2040 into the target volume 2042 to activate the medicant 2034.

In certain aspects, the systems and methods disclosed herein can utilize an anesthetic coupled with a non-anesthetic medicant, where the anesthetic can reduce pain and inflammation associated with application of the ultrasound energy, including pain and inflammation associated with the transdermal delivery of the medicant or other ultrasound-generated effects described herein.

In certain aspects, the medicant can be at least partially transparent to ultrasound energy. In certain aspects, the medicant can be substantially transparent to ultrasound energy.

In certain aspects, the stratum corneum layer 2014 can be substantially intact prior to the application of ultrasound energy. For example, prior to the application of ultrasound energy, the stratum corneum layer 2014 can have no punctures, microchannels, wounds, other means of improving permeability of a medicant, or combinations thereof.

The medicant can be mixed into or be a component of an acoustic coupling medium. In some embodiments, an acoustic coupling medium, such as an acoustic coupling gel or an acoustic coupling cream, can comprise the medicant. In some embodiments, a medicant is administered to a skin surface above the ROI. In some applications, the medicant can be the acoustic coupling medium. In some applications, the medicant can be a combination of medicants, such as any combination of those described herein.

A medicant can comprise an anesthetic. In some aspects, the anesthetic can comprise lidocaine, benzocaine, prilocaine, tetracaine, novocain, butamben, dibucaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, tetracaine, or any combination thereof. The anesthetic an eliminate or reduce the pain generated by the application of ultrasound energy to the skin, for example, the creation of the micro-channels in the skin by ultrasound energy. The anesthetic can constrict blood flow, which can eliminate or reduce any blood flowing that emerges to the skin surface by way of damage from the application of ultrasound energy to the skin, for example, blood flowing up a micro-channel generated by ultrasound energy and onto the skin surface. Further, the use of an anesthetic, such as lidocaine, in the acoustic coupling medium substantially eliminates skin irritation from the application of ultrasound energy, such as the ultrasound-induced creation of micro-channels penetrating the skin surface.

A medicant can comprise a drug, a vaccine, a nutraceatical, or an active ingredient. A medicant can comprise blood or a blood component, an allergenic, a somatic cell, a recombinant therapeutic protein, or any living cells that are used as therapeutics to treat diseases or as actives to produce a cosmetic or a medical effect. A medicant can comprise a biologic, such as for example a recombinant DNA therapy, synthetic growth hormone, monoclonal antibodies, or receptor constructs. A medicant can comprise stem cells.

A medicant can comprise adsorbent chemicals, such as zeolites, and other hemostatic agents are used in sealing severe injuries quickly. A medicant can comprise thrombin and/or fibrin glue, which can be used surgically to treat bleeding and to thrombose aneurysms. A medicant can comprise Desmopressin, which can be used to improve platelet function by activating arginine vasopressin receptor 1 A. A medicant can comprise a coagulation factor concentrates, which can be used to treat hemophilia, to reverse the effects of anticoagulants, and to treat bleeding in patients with impaired coagulation factor synthesis or increased consumption. A medicant can comprise a Prothrombin complex concentrate, cryoprecipitate and fresh frozen plasma, which can be used as coagulation factor products. A medicant can comprise recombinant activated human factor VII, which can be used in the treatment of major bleeding. A medicant can comprise tranexamic acid and/or aminocaproic acid, which can inhibit fibrinolysis, and lead to a de facto reduced bleeding rate. A medicant can comprise platelet-rich plasma (PRP), mesenchymal stem cells, or growth factors. For example, PRP is typically a fraction of blood that has been centrifuged. The PRP is then used for stimulating healing of the injury. The PRP typically contains thrombocytes (platelets) and cytokines (growth factors). The PRP may also contain thrombin and may contain fibenogen, which when combined can form fibrin glue.

In addition, a medicant can comprise a steroid, such as, for example, like the glucocorticoid cortisol. A medicant can comprise an active compound, such as, for example, alpha lipoic Acid, DMAE, vitamin C ester, tocotrienols, and/or phospholipids. A medicant can comprise a pharmaceutical compound such as for example, cortisone, Etanercept, Abatacept, Adalimumab, or Infliximab. A medicant can comprise Botox. A medicant can comprise lignin peroxidase, which can be derived from fungus and can be used for skin lightening applications. A medicant can comprise hydrogen peroxide, which can be used for skin lighting applications.

The medicant can comprise an anti-inflammatory agent, such as, for example, a non-steroidal anti-inflammatory drug (NSAID), such as aspirin, celecoxib (Celebrex), diclofenac (Voltaren), diflunisal (Dolobid), etodolac (Lodine), ibuprofen (Motrin), indomethacin (Indocin), ketoprofen (Orudis), ketorolac (Toradol), nabumetone (Relafen), naproxen (Aleve, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene), salsalate (Amigesic), sulindac (Clinoril), or tolmetin (Tolectin).

Still further, a medicant can comprise an active ingredient which provides a cosmetic and/or therapeutic effect to the area of application on the skin. Such active ingredients can include skin lightening agents, anti-acne agents, emollients, non-steroidal anti-inflammatory agents, topical anesthetics, artificial tanning agents, antiseptics, anti-microbial and anti-fungal actives, skin soothing agents, sunscreen agents, skin barrier repair agents, anti-wrinkle agents, anti-skin atrophy actives, lipids, sebum inhibitors, sebum inhibitors, skin sensates, protease inhibitors, skin tightening agents, anti-itch agents, hair growth inhibitors, desquamation enzyme enhancers, anti-glycation agents, compounds which stimulate collagen production, and mixtures thereof.

Other examples of such active ingredients can include any of panthenol, tocopheryl nicotinate, benzoyl peroxide, 3-hydroxy benzoic acid, flavonoids (e.g., flavanone, chalcone), farnesol, phytantriol, glycolic acid, lactic acid, 4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters (e.g., retinyl propionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopherol and its esters (e.g., tocopheryl acetate), azelaic acid, arachidonic acid, tetracycline, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4′-trichloro-2′-hydroxy diphenyl ether, 3,4,4′-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neomycin sulfate, theophylline, and mixtures thereof.

A medicant can be any natural or synthetic compound or any combination of compounds, or a drug, or a biologic, as described herein, or is known to one skilled in the art, or is developed in the future.

A medicant can be diluted with an appropriate solvent for delivery. For example, a medicant can be diluted or mixed with a solvent to lower viscosity to improve transfer of the medicant. For example, a medicant can be diluted or mixed with a solvent that is a vehicle for transfer of the medicant, such as, for example, mixing a medicant with a formulation of polyethylene glycol (PEG). In some applications, the medicant can be mixed with a solvent to improve a tissue effect, such as uptake into the tissue, such as, for example, mixing a medicant with dimethyl sulfoxide (DMSO). In some applications, the medicant can be mixed with a solvent, which can restrict or inhibit an ultrasound energy effect. For example, a medicant can be mixed with ethanol (EtOH), which inhibits the thermal effect of ablation. In some applications, the medicant can be mixed with a solvent, which can amplify an ultrasound energy effect. For example, a medicant can be mixed with a contrast agent, which can be configured to promote higher attenuation and/or cavitation at lower acoustic pressures.

A medicant can be in a non-liquid state. In some applications, a medicant can be a gel or a solid, which by using a thermal effect, can melt into a liquid state suitable for delivery. For example, a medicant can be mixed into a thermally responsive hydrogel, which is configured to transform into an injectable state upon receiving a suitable amount of thermal energy emitted from a transducer.

In some aspects, a medicant can be administered to a skin surface above the ROI. The medicant can be mixed into or be a component of an acoustic coupling medium. In some applications, the medicant can be the acoustic coupling medium. In some aspects, the acoustic coupling medium can comprise a preservative and/or a preservative enhancer, such as, for example, water-soluble or solubilizable preservatives including Germall 115, methyl, ethyl, propyl and butyl esters of hydroxybenzoic acid, benzyl alcohol, sodium metabisulfite, imidazolidinyl urea, EDTA and its salts, Bronopol (2-bromo-2-nitropropane- -1,3-diol) and phenoxypropanol; antifoaming agents; binders; biological additives; bulking agents; coloring agents; perfumes, essential oils, and other natural extracts.

In certain aspects, micro-channels 2060 can be long enough for fluid communication between the skin surface 2012 and the epidermis 2016. The micro-channels 2060 can have a diameter large enough to allow the medicant to pass from the skin surface 2012 to the epidermis 2016. The micro-channels 2060 can have a diameter small enough to prevent bleeding from subcutaneous tissue to the skin surface 2012.

In certain aspects, a single ultrasound pulse can provide sufficient effect to drive the medicant through the stratum corneum 2014. In some aspects, two more more ultrasound pulses, including but not limited to, two, three, four, five, six, seven, eight, nine, ten, or more ultrasound pulses can provide sufficient effect to drive the medicant through the stratum corneum 2014.

In certain aspects, the systems and methods described herein can drive medicant through the stratum corneum 2014 after application of ultrasound energy for a total length of time of less than 5 minutes, including but not limited to, less than 3 minutes, less than 1 minute, less than 50 seconds, less than 40 seconds, less than 30 seconds, less than 25 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, less than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds, or less than 1 second.

The systems and methods described herein can be employed in numerous clinical applications. For example, a treatment for scars can include a medicant directed by acoustic energy through micro-channels to a scar location. A second acoustic energy can be directed to the scar location and be configured to interact with the medicant to remodel and/or modify the scar tissue and eventually replace the scar tissue via remodeling. The treatment can also include directing therapeutic acoustic energy into the scar tissue. In some applications, the therapeutic acoustic energy can be configured to ablate a portion of the scar tissue, thereby removing a portion of the scar tissue. In some applications, the therapeutic acoustic energy can be configured to create a lesion in or near the scar tissue, thereby facilitating skin tightening above the lesion. In some applications, the therapeutic acoustic energy can be configured to remodel and/or increase an amount of collagen around the scar tissue, thereby replacing portions of the scar tissue with newly formed collagen.

In another example, the systems and methods described herein can be used in the treatment of hyperpigmentation. A medicant can be a skin lightening agent, which can be any active ingredient that improves hyperpigmentation. Without being bound by theory, use of skin lightening agents can effectively stimulate the epidermis, particularly the melanocyte region, where the melanin is generated. The combined use of the skin lightening agent and ultrasound energy can provide synergistic skin lightening benefit. A medicant comprise a skin lightening agent, such as, for example, ascorbic acid compounds, vitamin B3 compounds, azelaic acid, butyl hydroxyanisole, gallic acid and its derivatives, glycyrrhizinic acid, hydroquinone, kojic acid, arbutin, mulberry extract, and mixtures thereof. Use of combinations of skin lightening agents can be advantageous as they may provide skin lightening benefit through different mechanisms.

In one aspect, a combination of ascorbic acid compounds and vitamin B3 compounds can be used. Examples of ascorbic acid compounds can include L-ascorbic acid, ascorbic acid salt, and derivatives thereof. Examples of ascorbic acid salts include sodium, potassium, lithium, calcium, magnesium, barium, ammonium and protamine salts. Examples of ascorbic acid derivatives include for example, esters of ascorbic acid, and ester salts of ascorbic acid. Examples of ascorbic acid compounds include 2-O-D-glucopyranosyl-L-ascorbic acid, which is an ester of ascorbic acid and glucose and usually referred to as L-ascorbic acid 2-glucoside or ascorbyl glucoside, and its metal salts, and L-ascorbic acid phosphate ester salts such as sodium ascorbyl phosphate, potassium ascorbyl phosphate, magnesium ascorbyl phosphate, and calcium ascorbyl phosphate. In addition, medicant can comprise lignin peroxidase, which can be derived from fungus used for skin lightening applications. In another example, medicant can comprise hydrogen peroxide, which can be used for skin lighting applications.

In an exemplary application, a coupling agent can comprise a medicant, which comprises a skin lighting agent. Ultrasound energy can direct the lightening agent into the epidermis and into contact with melanin. The lightening agent can remove excess melanin. Additional ultrasound energy can be directed to the epidermis to provide a cavitation effect to break up the excess melanin pigment. In some examples, additional ultrasound energy can be directed to the epidermis to provide a thermal effect, which can be configured to increase the effectiveness of the skin lightening agent. In one example, the skin lightening agent can be hydrogen peroxide and the ultrasound energy can increase the temperature of the hydrogen peroxide by at least 1° C. and to about 15° C., which increases the effectiveness of the skin lightening agent.

In another example of a clinical application, the systems and methods described herein can be used in the treatment of hypopigmentation. In an exemplary application, a coupling agent can comprise a medicant, which can comprise a corticosteroid. Ultrasound energy can direct the corticosteroid into the epidermis at the light colored areas of the skin. A second ultrasound energy can be directed to the treatment location and be configured to interact with the corticosteroid to provide a synergistic treatment to increase pigment concentration at the treatment location. A second energy, such as, a photon-based energy from a laser can be directed to the treatment location to further increase the pigment concentration in the treatment location. A third energy, such as, ultrasound energy can be directed to the treatment location to disperse the generated pigment and provide an even coloring pattern at the treatment location.

In another example, large molecule medicants can be delivered using the systems and methods described herein. A large molecule can be greater than 500 Da. A large molecule can be any medicinal product manufactured in or extracted from biological sources. Examples of large molecule include vaccines, blood or blood components, allergenics, somatic cells, gene therapies, tissues, recombinant therapeutic protein and living cells. In one example, a large molecule comprises stem cells. An energy effect is provided by an acoustic energy field, which is configured to drive the large molecule through the micro-channels and into subcutaneous tissue. The energy effect can be acoustic streaming and/or inertial cavitation. In some applications, the energy effect is a thermal effect, which can be configured to lower the viscosity of a large molecule for improved transfer through the micro-channels.

In another example, chemotherapy drugs can be delivered using the systems and methods described herein. Some of the advantages, of using such systems and methods, include concentrating the chemotherapy drug to the tumor site (as opposed to exposing the whole body to the drug), lower doses may be required (due to the site specific treatment), and greater effectiveness of the drug.

In some applications, a chemotherapy drug can be a large molecule. In some applications, the systems and methods, described herein, can deliver anti-body drug conjugates, which target cancer stem cells to destroy a tumor. In some applications, a chemotherapy drug is a liposome encapsulated chemotherapy drug, which can be delivered through the micro-channels to a treatment site by an acoustic energy field, and then a second acoustic energy field can be delivered to melt the liposome and release the chemotherapy drug. In some applications, an acoustic energy field can be delivered, which is configured to provide micro-bubbles (cavitation) to a tumor in a treatment site without generating heat, which can lead to reduction or elimination of the tumor. These micro-bubbles can increase microvessel permeability of drugs, enhance drug penetration through the interstitial space, and increase tumor cell uptake of the drugs, thus enhancing the antitumor effectiveness of the drugs.

In some applications of chemotherapy, a drug-loaded nanoemulsion can be driven through the micro-channels to a tumor site via an acoustic energy field. A second acoustic energy field can be delivered to the tumor site and can be configured to trigger drug release from nanodroplets, which can be created by micro-bubbles. A third acoustic energy field can be delivered to the tumor site and can be configured to produce an energy effect, for example, a thermal effect and/or cavitation, which enhances uptake of the drug by the tumor.

In another example, photodynamic therapy can be delivered using the systems and methods described herein. As known to one skilled in the art, photodynamic therapy is a medical treatment that utilizes a medicant, which comprises a photosensitizing agent and a photon-emission source to activate the administered medicant. In some applications, the medicant comprising a photosensitizing agent is delivered through the micro-channels into tissue via an acoustic energy field. After the medicant has been delivered, a second acoustic energy field can be delivered to enhance permeability and/or uptake of the medicant by the tissue. After the medicant has been delivered, a photon energy field at a specific wavelength is delivered from the photon-emission source to the tissue, which activates the medicant. The photon-emission source can include, but are not limited to: laser, LED or intense pulsed light. The optimal photon-emission source is determined by the ideal wavelength for activation of the medicant and the location of the target tissue. The photon energy field is directly applied to the target tissue for a specific amount of time. The medicant can be Levulan, which is used for the treatment of skin cancer. The medicant can be Metvix, which is used for the treatment of skin cancer. The medicant can be Photofin, which is used for the treatment of bladder cancer, lung cancer and esophagus cancer. The medicant can be aminolevulinic acid, which has been used in the treatment of various skin conditions, such as, for example, acne, rosacea, sun damage, enlarged sebaceous glands, wrinkles, warts, hidradenitis suppurativa, and psoriasis.

In another example, injuries to muscles can be treated using the systems and methods described herein. For treating an injury to a muscle, ligament, or tendon, a medicant can comprise platelet-rich plasma (PRP), mesenchymal stem cells, or growth factors. For example, PRP is typically a fraction of blood that has been centrifuged. The PRP is then used for stimulating healing of the injury. The PRP typically contains thrombocytes (platelets) and cytokines (growth factors). The PRP may also contain thrombin and may contain fibenogen, which when combined can form fibrin glue. The medicant is directed through a micro-channels to the injury, such as, for example a tear in the tissue. An acoustic energy field can then be directed to the injury to activate the medicant and/or disperse the medicant. The acoustic energy field can create a thermal effect to heat the injury location which can initiate interaction of the medicant with the tissue at the injury location and/or increase blood perfusion in the injury location. The acoustic energy field can ablate a portion of tissue in the injury location, which can peak inflammation and increase the speed of the healing process. The acoustic energy field can be directed to the injury location and weld together the tear using both an ablative thermal effect and various mechanical effects.

In an example, acne can be treated using the systems and methods described herein. A medicant can comprise any one or more of cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters (e.g., retinyl propionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopherol and its esters (e.g., tocopheryl acetate), azelaic acid, arachidonic acid, tetracycline, ibuprofen, naproxen, ketoprofen, hydrocortisone, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4′-trichloro-2′-hydroxy diphenyl ether, 3,4,4′-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neomycin sulfate, theophylline. The medicant is directed through the micro-channels to a ROI comprising a sebaceous gland. The medicant interacts with bacteria in the sebaceous gland to reduce or eliminate the bacteria responsible for acne. An acoustic energy field can provide a mechanical effect to disperse the medicant into one or more sebaceous gland. An acoustic energy field can provide a thermal effect to accelerate the reaction of the medicant to eliminate or reduce the amount of bacteria in the sebaceous gland. An acoustic energy field can provide a thermal effect to injure or destroy at least a portion of the sebaceous gland. A photon based energy field can be directed to the medicant in the ROI to initiate a photodymanic effect to activate the medicant. A photon based energy field can be directed to the medicant in the ROI to reduce photosensitivity of the tissue in the ROI from sunlight.

As used herein, pulse width is the time from the start of the pulse to the end of the pulse measured at a −3 dB or −6 dB power point.

As used herein, “acoustic streaming” refers to a force of acoustic energy which displaces a material through a tissue environment.

EXAMPLE 1

An ultrasound transducer was coupled to a forearm of two human patients with a standard acoustic coupling gel in one location and a 5% topical solution of lidocaine as an acoustic coupling gel in a second location. The 5% topical solution of lidocaine had negligible acoustic attenuation of less than 1 dB/cm/MHz. The ultrasound transducer transmitted ultrasound energy at 10 MHz, a pulse width of 25 ms, and an energy of 0.5 J. The ultrasound energy was focused to a depth of 1.5 mm beneath the surface of human skin. The presence of the 5% topical solution of lidocaine reduced pain from the application of the ultrasound energy by approximately 2 points on a 10-point pain scale when compared with the application of the ultrasound energy in the absence of the lidocaine. Referring to FIG. 10A, the ultrasound energy was applied in treatment lines to an area on the left with only the standard acoustic coupling gel present and the same ultrasound energy was applied to an area on the right with the 5% lidocaine solution present on the skin surface. Referring to FIG. 10B, the ultrasound energy was applied in treatment lines to an area on the right with only the standard acoustic coupling gel present and the same ultrasound energy was applied to an area on the left with a 5% lidocaine ointment present on the skin surface. FIGS. 10A and 10B show evidence of the treatment effect of lidocaine in this disclosure. After the application of the ultrasound energy, the treatment areas that did not have lidocaine applied to them were irritated, red, and welt-like, whereas the treatment areas that did have lidocaine applied to them were smooth and contained barely visible remnants. The ultrasound energy that was utilized exhibited broadband spectral properties when applied to water, gel, and tissue, which is evidence of an inertial cavitation effect.

EXAMPLE 2

An ultrasound transducer was coupled to an ex-vivo sample of pig skin with dyed water as a coupling agent. The water was dyed with a green food dye. The ultrasound transducer transmitted ultrasound energy in treatment lines of high intensity ultrasound point exposures at a frequency of 2.87 MHz, a pulse width of 170 ms, and a pulse power of 10 W. The ultrasound energy was focused to a depth of approximately 1.5 mm beneath the surface of the pig skin. Locations that were not treated with the ultrasound energy showed penetration of the dye ranging from 1.0 mm to 1.5 mm. Locations that were treated with the ultrasound energy showed penetration of the dye ranging from 2.0 mm to 2.8 mm, thereby showing that the application of the ultrasound energy enhanced the transdermal transport of the water containing the dye. The ultrasound energy that was utilized exhibited broadband spectral properties when applied to water, gel, and tissue, which is evidence of an inertial cavitation effect.

The present disclosure has been described above with reference to various exemplary configurations. However, those skilled in the art will recognize that changes and modifications may be made to the exemplary configurations without departing from the scope of the present invention. For example, the various operational steps, as well as the components for carrying out the operational steps, may be implemented in alternate ways depending upon the particular application or in consideration of any number of cost functions associated with the operation of the system, e.g., various of the steps may be deleted, modified, or combined with other steps. Further, it should be noted that while the method and system for ultrasound treatment as described above is suitable for use by a medical practitioner proximate the patient, the system can also be accessed remotely, i.e., the medical practitioner can view through a remote display having imaging information transmitted in various manners of communication, such as by satellite/wireless or by wired connections such as IP or digital cable networks and the like, and can direct a local practitioner as to the suitable placement for the transducer. Moreover, while the various exemplary embodiments may comprise non-invasive configurations, system can also be configured for at least some level of invasive treatment application. These and other changes or modifications are intended to be included within the scope of the present invention, as set forth in the following claims. 

1. A method for ultrasound-assisted delivery of a medicant through a stratum corneum layer of a skin surface, the method comprising: a) administering the medicant to the skin surface; b) coupling an ultrasound transducer to the medicant and the skin surface; and c) applying a first pulsed acoustic energy field from the ultrasound transducer to the skin surface, the first pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 100 W/cm² to 100 kW/cm², and a pulse width from 33 nanoseconds to 5 seconds, the first pulsed acoustic energy field generating inertial cavitation, acoustic streaming, or a combination thereof in the stratum corneum layer and driving the medicant through the stratum corneum layer.
 2. The method according to claim 1, wherein the first pulsed acoustic energy field is applied for sufficient time to drive an amount of medicant through the stratum corneum layer sufficient to achieve a clinical effect in a tissue beneath the stratum corneum layer.
 3. The method according to claim 1, wherein the first pulsed ultrasound energy has a pulse repetition rate from one pulse per 10 microseconds to one pulse per 100 seconds.
 4. The method according to claim 1, wherein the first pulsed acoustic energy field creates a thermal effect in a tissue beneath the stratum corneum layer, thereby raising a temperature of the tissue from 1° C. to 15° C.
 5. The method according to claim 1, the method further comprising: d) applying an alternating pulsed acoustic energy field between pulses of the first pulsed acoustic energy field, the alternating pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 5 W/cm² to 100,000 W/cm², and a pulse width from 1 microsecond to 0.1 seconds, the first pulsed acoustic energy field and the alternating pulsed acoustic energy field generating inertial cavitation, acoustic streaming, or a combination thereof in the stratum corneum layer and driving the medicant through the stratum corneum layer.
 6. The method according to claim 1, the method further comprising: d) focusing a second pulsed acoustic energy field to a target volume at a depth beneath the stratum corneum layer, the second acoustic energy field configured to generate a thermal effect in the target volume, thereby ablating at least a portion of the target volume.
 7. The method according to claim 6, wherein the thermal effect raises a temperature in the target volume by from 15° C. to 65° C. without damaging an intervening tissue between the skin surface and the target volume.
 8. The method according to claim 1, the method further comprising: d) applying a second pulsed acoustic energy field focused to a depth beneath the skin surface, wherein the second pulsed acoustic energy field is emitted from the ultrasound transducer or a different ultrasound transducer, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, an intensity from 5 W/cm² to 70,000 W/cm², and a pulse width from 33 nanoseconds to 1 second, thereby creating acoustic streaming having a pressure from 10 kPa to 100 MPa and driving the medicant through an epidermis layer and into a dermis layer.
 9. The method according to claim 8, wherein the first pulsed acoustic energy field or the second pulsed acoustic energy field creates a thermal effect in the epidermis layer or the dermis layer, the thermal effect elevating a temperature by 1° C. to 15° C.
 10. The method according to claim 9, wherein the thermal effect increases blood perfusion within the epidermis layer or the dermis layer, thereby increasing absorption of the medicant into a bloodstream.
 11. The method according to claim 1, the method further comprising: d) applying a second pulsed acoustic energy field configured to provide an inertial cavitation effect at a depth of 0.5 millimeter to 7 millimeters beneath the skin surface, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 3 W/cm² to 100 kW/cm², and a pulse width from 33 nanoseconds to 100 seconds, thereby increasing dispersion of the medicant in an epidermis layer or a dermis layer beneath the skin surface.
 12. A method for reducing or eliminating pain generated by ultrasound treatment, the method comprising: a) applying a coupling medium comprising a medicant to a skin surface above a region of interest, the medicant comprising an anesthetic configured to numb a tissue in the region of interest; b) coupling an ultrasound energy source to the coupling medium, the skin surface, and the region of interest; c) directing a first acoustic energy field from the ultrasound energy source into the skin surface, thereby delivering the medicant into the tissue in the region of interest and numbing the tissue in a portion of the region of interest; and d) directing a second acoustic energy field to a target volume in the tissue in the region of interest, the second acoustic energy field ablating the tissue in the target volume, the medicant reducing or eliminating pain generated by the ablating of the tissue.
 13. The method according to claim 12, wherein the first ultrasound energy has one or more of the following properties: a frequency from 1 MHz to 30 MHz; a peak intensity from 100 W/cm² to 100,000 W/cm²; a pulse width from 33 nanoseconds to 5 seconds; and a pulse repetition rate from one pulse per 10 microseconds to one pulse per 100 seconds.
 14. The method according to claim 12, wherein the first acoustic energy field creates a thermal effect in the tissue in the region of interest, thereby raising a temperature of the tissue from 1° C. to 15° C.
 15. The method according to claim 12, the method further comprising: e) applying a third acoustic energy field configured to provide an inertial cavitation effect in the target zone, the third acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 3 W/cm² to 100 kW/cm², and a pulse width from 33 nanoseconds to 100 seconds, thereby dispersing the medicant in the target zone.
 16. The method according to claim 12, the method further comprising: e) coupling a second ultrasound energy source to the coupling medium, the skin surface, and the region of interest, the second acoustic energy field is generated by the second ultrasound energy source.
 17. The method according to claim 12, wherein the second acoustic energy field is generated by the ultrasound energy source.
 18. The method according to claim 12, wherein the anesthetic is selected from the group consisting of lidocaine, benzocaine, prilocaine, tetracaine, novocain, butamben, dibucaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, tetracaine, and combinations thereof.
 19. A method of ultrasound-assisted transdermal drug delivery, the method comprising: a) contacting a skin surface with a coupling medium comprising a non-anesthetic medicant and an anesthetic; b) coupling an ultrasound energy source to the coupling medium and the skin surface; c) applying a first pulsed acoustic energy field from the ultrasound transducer to the skin surface, the first pulsed acoustic energy field having a peak intensity from 100 W/cm² to 100 kW/cm², thereby driving the medicant and the anesthetic across a stratum corneum layer of the skin surface and into an epidermis layer beneath the skin surface, the anesthetic alleviating pain or swelling associated with the application of the first pulsed acoustic energy field.
 20. The method according to claim 19, wherein the first pulsed acoustic energy field has one or more of the following properties: a frequency from 1 MHz to 30 MHz; a pulse width from 33 nanoseconds to 5 seconds; and a pulse repetition rate from one pulse per 10 microseconds to one pulse per 100 seconds.
 21. The method according to claim 19, wherein the first pulsed acoustic energy field creates a thermal effect in a target zone of the epidermis layer, thereby raising a temperature of the target zone from 1° C. to 15° C.
 22. The method according to claim 19, the method further comprising: d) applying an alternating pulsed acoustic energy field between pulses of the first pulsed acoustic energy field, the alternating pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 5 W/cm² to 100,000 W/cm², and a pulse width from 33 nanoseconds to 0.1 seconds, the first pulsed acoustic energy field and the alternating pulsed acoustic energy field generating inertial cavitation, acoustic streaming, or a combination thereof in the stratum corneum layer and driving the medicant through the stratum corneum layer.
 23. The method according to claim 19, the method further comprising: d) focusing a second pulsed acoustic energy field to a target volume within the epidermis layer, the second acoustic energy field configured to generate a thermal effect in the target volume, thereby ablating at least a portion of the target volume.
 24. The method according to claim 23, wherein the thermal effect raises a temperature in the target volume by from 15° C. to 65° C. without damaging an intervening tissue between the skin surface and the target volume.
 25. The method according to claim 19, the method further comprising: d) applying a second pulsed acoustic energy field focused to a depth within the epidermis layer, wherein the second pulsed acoustic energy field is emitted from the ultrasound transducer or a different ultrasound transducer, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, an intensity from 5 W/cm² to 70,000 W/cm², and a pulse width from 33 nanoseconds to 1 second, thereby creating acoustic streaming having a pressure from 10 kPa to 100 MPa and driving the medicant through the epidermis layer and into a dermis layer.
 26. The method according to claim 25, wherein the first pulsed acoustic energy field or the second pulsed acoustic energy field creates a thermal effect in the epidermis layer or the dermis layer, the thermal effect elevating a temperature by 1° C. to 15° C.
 27. The method according to claim 26, wherein the thermal effect increases blood perfusion within the epidermis layer or the dermis layer, thereby increasing absorption of the medicant into a bloodstream.
 28. The method according to claim 25, the method comprising: d) focusing a third pulsed acoustic energy field to a target volume within the dermis layer, the third acoustic energy field configured to generate a thermal effect in the target volume, thereby ablating at least a portion of the target volume.
 29. The method according to claim 28, wherein the thermal effect raises a temperature in the target volume by from 15° C. to 65° C. without damaging an intervening tissue between the skin surface and the target volume.
 30. The method according to claim 19, the method further comprising: d) applying a second pulsed acoustic energy field configured to provide an inertial cavitation effect at a depth of 0.5 millimeter to 7 millimeters beneath the skin surface, the second pulsed acoustic energy field having a frequency from 1 MHz to 30 MHz, a peak intensity from 3 W/cm² to 100 kW/cm², and a pulse width from 33 nanoseconds to 100 seconds, thereby increasing dispersion of the medicant in an epidermis layer or a dermis layer beneath the skin surface. 